Molecular and Pathologic Characterization of YAP1-Expressing Small Cell Lung Cancer Cell Lines Leads to Reclassification as SMARCA4-Deficient Malignancies

Ng, J; Cai, L; Girard, L; Prall, OWJ; Rajan, N; Khoo, C; Batrouney, A; Byrne, DJ; Boyd, DK; Kersbergen, AJ; Christie, M; Minna, JD; Burr, ML; Sutherland, KD

Author(s): Ng, J; Cai, L; Girard, L; Prall, OWJ; Rajan, N; Khoo, C; Batrouney, A; Byrne, DJ; Boyd, DK; Kersbergen, AJ; Christie, M; Minna, JD; Burr, ML; Sutherland, KD;
Details: Publication Year 2024-01-05,Volume 30,Issue #9,Page 1846-1858
Journal Title: Clinical Cancer Research
Abstract: PURPOSE: The classification of small cell lung cancer (SCLC) into distinct molecular subtypes defined by ASCL1, NEUROD1, POU2F3, or YAP1 (SCLC-A, -N, -P, or -Y) expression, paves the way for a personalized treatment approach. However, the existence of a distinct YAP1-expressing SCLC subtype remains controversial. EXPERIMENTAL DESIGN: To better understand YAP1-expressing SCLC, the mutational landscape of human SCLC cell lines was interrogated to identify pathogenic alterations unique to SCLC-Y. Xenograft tumors, generated from cell lines representing the four SCLC molecular subtypes, were evaluated by a panel of pathologists who routinely diagnose thoracic malignancies. Diagnoses were complemented by transcriptomic analysis of primary tumors and human cell line datasets. Protein expression profiles were validated in patient tumor tissue. RESULTS: Unexpectedly, pathogenic mutations in SMARCA4 were identified in six of eight SCLC-Y cell lines and correlated with reduced SMARCA4 mRNA and protein expression. Pathologist evaluations revealed that SMARCA4-deficient SCLC-Y tumors exhibited features consistent with thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT). Similarly, the transcriptional profile SMARCA4-mutant SCLC-Y lines more closely resembled primary SMARCA4-UT, or SMARCA4-deficient non-small cell carcinoma, than SCLC. Furthermore, SMARCA4-UT patient samples were associated with a YAP1 transcriptional signature and exhibited strong YAP1 protein expression. Together, we found little evidence to support a diagnosis of SCLC for any of the YAP1-expressing cell lines originally used to define the SCLC-Y subtype. CONCLUSIONS: SMARCA4-mutant SCLC-Y cell lines exhibit characteristics consistent with SMARCA4-deficient malignancies rather than SCLC. Our findings suggest that, unlike ASCL1, NEUROD1, and POU2F3, YAP1 is not a subtype defining transcription factor in SCLC.
Publisher: AACR
Keywords: Humans; *Small Cell Lung Carcinoma/genetics/pathology/metabolism; *Transcription Factors/genetics; *DNA Helicases/genetics; *Nuclear Proteins/genetics; Cell Line, Tumor; Animals; *Adaptor Proteins, Signal Transducing/genetics; *YAP-Signaling Proteins/genetics; *Mutation; Mice; *Lung Neoplasms/genetics/pathology/metabolism; Gene Expression Regulation, Neoplastic; Phosphoproteins/genetics; Biomarkers, Tumor/genetics; Gene Expression Profiling
Research Division(s): Cancer Biology And Stem Cells
PubMed ID: 38180245
Publisher's Version: https://doi.org/10.1158/1078-0432.Ccr-23-2360
Open Access at Publisher's Site: https://doi.org/10.1158/1078-0432.CCR-23-2360
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-01-25 09:18:06

Last Modified: 2024-05-09 09:00:53